Maple Syrup Urine Disease

Other Names

Branched-chain ketoaciduria

Branched-chain ketoacid dehydrogenase (BCKD) deficiency

Diagnosis Coding

E71.0, maple-syrup-urine disease

Disorder Category

An amino acidemia



Elevated leucine and leucine/alanine ratio

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=100%; specificity=99.99%; milder forms of the disease can be missed by newborn screening. [Schulze: 2003] [Puckett: 2010]


Maple syrup urine disease (MSUD) is caused by a defect in branched-chain ketoacid dehydrogenase (BCKD), which is a multi-enzyme complex with 4 components found in mitochondria in liver, kidney, muscle, and fibroblasts. The enzyme is responsible for the degradation of oxoacids. Accumulation of leucine and its corresponding branched-chain keto acid (BCKA), alpha-ketoisocaproic acid (alpha KIC), disturbs brain cell volume regulation with consequent brain edema and secondary impairment of neuron growth, myelin synthesis, and cerebral neurotransmitter production. These can cause death, intellectual and other disability.


The incidence of MSUD in the USA is approximately 1:198,000. [Therrell: 2014]


Autosomal recessive

Prenatal Testing

DNA testing or enzyme analysis by amniocentesis or CVS

Other Testing

DNA testing may be possible if the mutation is known.

Clinical Characteristics

With treatment before crises, normal IQ and development can be expected. Without treatment, profound mental retardation and neurologic disturbances can be expected. Brain edema can lead to cerebellar herniation, compression of the brain stem, and death, especially in older individuals.

Initial symptoms, beginning with protein ingestion, may include:
  • A maple syrup odor of cerumen, which can be present by 3 days of age
  • Elevated branched-chain amino acids, leucine, isoleucine, and valine; presence of allo-isoleucine detectable shortly after birth, but can be missed by the newborn screening in milder forms of the disease or if the sample is obtained too early (<12h after birth)
  • Ketonuria becomes evident after branched-chain amino acids become elevated
By 4-10 days, symptoms include:
  • Irritability, poor feeding, vomiting
  • Lethargy
  • Intermittent apnea
  • Arching
  • Repetitive "fencing" or "bicycling" movements
  • Coma and central respiratory failure
Because of the rapidity of onset, severe symptoms may be present before screening results are reported or treatment begins.
Variant forms of the disease may have milder and later onset of symptoms and present with anorexia, poor growth, irritability, or developmental delay in late infancy or childhood. Symptoms and metabolic crisis episodes may be precipitated by illnesses. Urine may also have a maple syrup odor, especially during metabolic crisis. One variant is responsive to thiamine.

Follow-up Testing after Positive Screen

Plasma amino acids (elevated leucine, isoleucine, alloleucine, valine); urine organic acid analysis (abnormal branched-chain ketoacids); hyperalimentation may cause abnormal results (elevated Leucine). Hydroxyprolinemia, a benign condition, can cause abnormal newborn screening for MSUD since hydroxyproline has the same mass/charge ratio of leucine/isoleucine.

Primary Care Management

Upon Notification of the + Screen

If the Diagnosis is Confirmed

  • Educate the family about signs, symptoms, and the need for urgent care if the infant becomes ill. See Maple Syrup Urine Disease - Information for Parents (STAR-G).
  • Support initiation and maintenance of dietary restriction of branched-chain amino acids (found in animal and vegetable food sources) and use of medical formulas. Provide protein as essential, and non-essential amino acids and supplementation with isoleucine or valine as needed.
  • Consider thiamine for children with the thiamine-responsive variant.
  • See patients readily when illness occurs since that is the primary cause of decompensation. Facilitate monitoring of urinary BCKA excretion with DNPH reagent strips at home. Measure amino acid levels through blood tests when indicated.
  • Admit to the hospital and seek expert assistance for management for any decompensation that does not promptly respond to outpatient treatment.
  • Assist in management of irreversible consequences as necessary, particularly with developmental and educational interventions.
  • See the Portal’s Maple Syrup Urine Disease (MSUD).

Specialty Care Collaboration

Provide initial consultation and ongoing collaboration, particularly for dietary management and management of decompensation episodes. Liver transplantation can be effective therapy that allows unrestricted diet and possibly prevents neurologic deterioration. Facilitate genetic counseling for the family.


Information & Support

For Professionals

Maple Syrup Urine Disease (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Maple Syrup Urine Disease (MSUD) (NECMP)
Guideline for clinicians treating the sick infant/child who has previously been diagnosed with maple syrup urine disease (MSDU); developed under the direction of Dr. Harvey Levy, Senior Associate in Medicine/Genetics at Children’s Hospital Boston, and Professor of Pediatrics at Harvard Medical School, for the New England Consortium of Metabolic Programs. Click PDF to view the complete protocol.

Genetics in Primary Care Institute (AAP)
Contains health supervision guidelines and other useful resources for the care of children with genetic disorders; American Academy of Pediatrics.

For Parents and Patients


Maple Syrup Urine Disease Family Support Group
A non-profit organization that provides information, newsletters and articles, family stories, support services, recipes and formulas, and dietary resources.


Maple Syrup Urine Disease - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of a newborn disorder; Screening, Technology and Research in Genetics.

Maple Syrup Urine Disease (MedlinePlus)
Information for families includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.


ACT Sheet for Maple Syrup Urine Disease (ACMG) (PDF Document 369 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Confirmatory Algorithm for MSUD (ACMG)
A resource for clinicians to help confirm diagnosis; American College of Medical Genetics.

Services for Patients & Families in New Mexico (NM)

Genetics clinic services throughout the US can be found through the Genetics Clinic Services Search Engine (ACMG).

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: March 2007; last update/revision: December 2015
Current Authors and Reviewers:
Author: Nicola Longo, MD, Ph.D.

Page Bibliography

Puckett RL, Lorey F, Rinaldo P, Lipson MH, Matern D, Sowa ME, Levine S, Chang R, Wang RY, Abdenur JE.
Maple syrup urine disease: further evidence that newborn screening may fail to identify variant forms.
Mol Genet Metab. 2010;100(2):136-42. PubMed abstract

Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF.
Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.
Pediatrics. 2003;111(6 Pt 1):1399-406. PubMed abstract

Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text